Radiofrequency Energy for PFO ClosureSuccessful Thermal Coaptation of

Patent Foramen Ovale: First Experience and Temporal Histopathologic Healing in a Porcine Model

Radiofrequency Energy for PFO ClosureRadiofrequency Energy for PFO ClosureSuccessful Thermal Coaptation of Successful Thermal Coaptation of

Patent Foramen Ovale: First Experience and Temporal Patent Foramen Ovale: First Experience and Temporal Histopathologic Healing in a Porcine ModelHistopathologic Healing in a Porcine Model

Hidehiko Hara MDHidehiko Hara MD11, Elena Ladich MD, Elena Ladich MD22, Renu Virmani MD, Renu Virmani MD22, , David Auth PhDDavid Auth PhD33, Joseph Eichinger, Joseph Eichinger33,, Robert S. Schwartz MDRobert S. Schwartz MD44

11Toho University Medical Center Ohashi Hospital, Tokyo, Toho University Medical Center Ohashi Hospital, Tokyo, 22CV Path, International Registry of Pathology, Gaithersburg, MD, CV Path, International Registry of Pathology, Gaithersburg, MD, 33CoAptus Medical Corporation, Redmond, WA, CoAptus Medical Corporation, Redmond, WA, 44Minneapolis Heart Institute and Foundation, Minneapolis, MNMinneapolis Heart Institute and Foundation, Minneapolis, MN

Disclosure statementDisclosure statement

Hidehiko Hara MDHidehiko Hara MD Consultant of Japan Lifeline Consultant of Japan Lifeline

Elena Ladich MDElena Ladich MD Nothing to discloseNothing to disclose

Renu Virmani MDRenu Virmani MD Nothing to discloseNothing to disclose

David Auth PhDDavid Auth PhD Consultant and ShareholderConsultant and Shareholder

Joseph EichingerJoseph Eichinger Employee of CoAptusEmployee of CoAptus

Robert S. Schwartz MDRobert S. Schwartz MD Consultant and ShareholderConsultant and Shareholder

Percutaneous patent foramen ovale (PFO) closure with implantable devices is commonly used, and limits embolic complications.

However, implantable closure devices placed across the atrial septum may exhibit thrombosis, device fracture or embolization.

A novel PFO closure strategy uses radiofrequency (RF)-based thermal energy to seal PFO without implanted devices.

Percutaneous patent foramen ovale (PFO) closure with implantable devices is commonly used, and limits embolic complications.

However, implantable closure devices placed across the atrial septum may exhibit thrombosis, device fracture or embolization.

A novel PFO closure strategy uses radiofrequency (RF)-based thermal energy to seal PFO without implanted devices.

BackgroundBackground

Hara H. et al. J Am Coll Cardiol 2005;46:1768 –76

Background Background

Movat x4

Movat x1.25

Background Background

H&E x10

H&E x10

Movat x10

Movat x10

HumanHuman

SwineSwine

Hara H. et al. Catheter Cardiovasc Interv 2007 ;69:266-73.

BackgroundBackground

RA

Movat x20

RA

Movat x20

HumanHumanSwineSwine

Hara H. et al. Catheter Cardiovasc Interv 2007 ;69:266-73.

Thirteen (13) domestic swine were studied over time following thermal PFO closure. Three animals were euthanized within 1 hour, 5 after 7 days, and 5 at 28 days. Gross and histopathologic findings were examined.

Thirteen (13) domestic swine were studied over time following thermal PFO closure. Three animals were euthanized within 1 hour, 5 after 7 days, and 5 at 28 days. Gross and histopathologic findings were examined.

MethodsMethods

Time post treatmentSacrifice

1 hour

7 days

28 days

Number of swine treated

3

5

5

Gross Pathological examination 1Gross Pathological examination 1

MethodsMethods

Major organs,Major organs,

Major great vesselsMajor great vessels

were assessed were assessed

for embolizationfor embolization

Heart, Heart, lungs, lungs, liver, liver, spleen,spleen,kidneys, kidneys, brain,brain,aorta, aorta, pulmonary arteriespulmonary arteries

Histopathological Examination Histopathological Examination MethodsMethods

Four to six tissue sections (4Four to six tissue sections (4--5 mm thick) 5 mm thick) were obtained from the treated PFO area. were obtained from the treated PFO area. The tissue sections were taken The tissue sections were taken perpendicular to the interatrial septum and perpendicular to the interatrial septum and submitted from anterior to posterior, submitted from anterior to posterior, starting with the posterior aspectstarting with the posterior aspectof the aorta (anterior margin) and included of the aorta (anterior margin) and included the atrial septum superior to the treated the atrial septum superior to the treated area as well as the ventricular septum with area as well as the ventricular septum with a portion of attached mitral and/or a portion of attached mitral and/or tricuspid valves for orientation.tricuspid valves for orientation.

TricuspidValve

TricuspidValve

Histological examination Histological examination

MethodsMethods

All tissue sections were cut at 4All tissue sections were cut at 4--6 6 microns using a rotary microtome, microns using a rotary microtome, mounted on a charged slide and stained mounted on a charged slide and stained with Hematoxylin & Eosin (H&E) and with Hematoxylin & Eosin (H&E) and Movat pentachrome. Movat pentachrome.

All sections were examined by light All sections were examined by light microscopy for thrombus, hemorrhage, microscopy for thrombus, hemorrhage, foreign material, inflammation, necrosis, foreign material, inflammation, necrosis, calcification and healing (calcification and healing (granulation granulation tissuetissue and and fibrosisfibrosis).).

epi

*RA

LA

MV

TCV

AS

VS

PFO

Superior

Inferior

Left Right

Gross Pathological examination 1Gross Pathological examination 1

ResultsResults

Heart, Heart, lungs, lungs, liver, liver, spleen,spleen,kidneys, kidneys, brain,brain,aorta, aorta, pulmonary arteriespulmonary arteries

No evidence of No evidence of myocardial myocardial infarctioninfarction

No No thromboembolic thromboembolic events events

Gross Pathological examination 2Gross Pathological examination 2Results: Day Zero Results: Day Zero

LA RA

Foramen ovale typically showed focal, small hemorrhagic lesions Foramen ovale typically showed focal, small hemorrhagic lesions on the right atrial side with brown friable material within tunnon the right atrial side with brown friable material within tunnel; el; grossly, all fossa appeared sealedgrossly, all fossa appeared sealed

Gross Pathological examination 2Gross Pathological examination 2LA RA

The left atrium showed The left atrium showed irregular tan brown irregular tan brown lesions opposite the lesions opposite the treatment sitetreatment siteGrossly the fossa were Grossly the fossa were sealedsealed

Results: Day 7 Results: Day 7

Treated areas of the Treated areas of the foramen ovale showed foramen ovale showed tan white and slightly tan white and slightly puckered lesions.puckered lesions.

Gross Pathological examination 2Gross Pathological examination 2Results: Day 28Results: Day 28

LA RA

Foramen ovale typically showed small tanForamen ovale typically showed small tan--white scars.white scars.The left atrium showed no gross lesions and the fossa The left atrium showed no gross lesions and the fossa were grossly sealedwere grossly sealed

Histopathological examination Histopathological examination Results: Day ZeroResults: Day Zero

Higher magnification shows coagulative myocyte necrosis and marked tissue edema. Platelet thrombus is noted within the tunnel beneath the flap on the left atrial side.

Boxed area of atrial septum shows Transmural effect.

Hara H. et al. Circulation . 2007 ;116:648-53.

Histopathological examination Results: Day 7

Higher magnification shows calcified myocytes (Ca) and chronic inflammationincluding giant cells adjacent to granulation tissue.

Whole mount Movat stained section shows rim of granulation tissue occupying >3/4 of the atrial septum.

Hara H. et al. Circulation . 2007 ;116:648-53.

Histopathological examination Results: Day 28

Higher magnification of granulation tissue consisting of fibroblasts, collagen, vascular channels (neovascularization)

RF based PFO closure is feasible, safe, and effective in swine.

Thermal healing, consisting of collagen formation, is nearly complete by 4 weeks.

This technique may allow substantial reduction in PFO closure risk over current device-based therapy.

Conclusions